Effect of Urine Flow Rate on Uric Acid Excretion in Man

Transcription

1 Effect of Urine Flow Rate on Uric Acid Excretion in Man Herbert S. Diamond, Robert Lazarus, David Kaplan and David Halberstam The effect of alteration in rate of urine flow on renal excretion of uric acid was studied with 29 clearance studies in 12 subjects. Uric acid excretion was found to increase with increase in urine flow. The relative contributions of changes in reabsorption and secretion to the observed increment in urate excretion were estimated by measuring the decrement in urate excretion produced by pyrazinamide, an inhibitor of renal tubular secretion. On the basis of these studies, the increment in uric acid excretion occurring during increased urine flow was attributed almost entirely to enhanced tubular secretion of urate as long as substantial extracellular fluid volume expansion was avoided. Extracellular fluid volume expansion was associated with decreased tubular reabsorption of urate. Since stimulation of the tubular transport system for urate by water ingestion is considered unlikely, this study was interpreted as consistent with the existence of a second, postsecretory distal tubular reabsorptive site for urate. Variation in urine flow rate must be taken into account in the interpretation of studies of renal handling of uric acid in man. According to present concepts, renal excretion of uric acid in man is a threecomponent system consisting of filtration, reabsorption and secretion (1). Uric acid is freely filtered at the From the Department of Medicine, State University of New York Downstate Medical Center, Brooklyn, NY. This work was presented at the Annual Meeting of the American Rheumatism Association, June 15, 197 I, New York, NY. This work was supported in part by US Public Health Service Grant RR and Arthritis Foundation Grant HERBERT s. DIAMOND, MD: Assistant Professor, Rheumatic Disease Section. Department of Medicine, State University of New York, Downstate Medical Center, Brooklyn, NY; ROBERT LAZARUS, MD: Fellow in Arthritis, Rheumatic Disease Section, Department of Medicine, State University of New York, Downstate Medical Center, Brooklyn, NY; DAVID KAPI AN, UD: Associate Professor, Rheumatic Disease Section, Department of Medicine, State University of New York Downstate Medical Center, Brooklyn, NY; DAVID HALBERSTAM, MA: Rheumatic Disease Section, Department of Medicine, State University of New York Downstate Medical Center. Brooklyn, NY. Reprint requests should be addressed to Dr. Herbert S. Diamond, State University of New York Downstate Medical Center, 450 Clarkson Avenue, Box 42, Brooklyn, NY Submitted for publication Dec 20, 1971 ; accepted March glomerulus (2). The proximal tubule is thought to be the site of bidirectional uric acid transport, consisting of the reabsorption of approximately 98% of the filtered load, and tubular secretion, which accounts for at least 80% of total urate excretion (36). It is possible to estimate the relative contribution of tubular reabsorption and secretion by measuring the decrement in urate excretion produced by pyrazinamide, an inhibitor of renal tubular secretion of uric acid (5, 7). Recent studies in the rat have provided evidence for distal tubular urate reabsorption in this species (8). Induction of a water diuresis results in a decrease in tubular fluid transit time and decreased urate concentration in the distal tubule and collecting duct. This might be expected to result in increased uric acid excretion if a distal reabsorptive site is operative in man. In 1937 BrochnerMortenson (9) reported that increased urine flow resulted in increased urate excretion in man. Several other reports have been consistent with a relationship be 338 Arthritis and Rheumatism, Vol. 15, No. 4 (JulyAugust 1972)

2 URINE ACID EXCRETION tween distal tubular flow and alteration of urate excretion (1 01 2). Changes in urate excretion which are secondary to changes in extracellular volume and urine flow rate have generally been thought to result from altered urate reabsorption. If the decreased urate reabsorption were occurring at a distal tubular site, it would appear as increased tubular secretion when interpreted on the basis of a threecomponent system. The present studies examine the effect of a water diuresis on renal excretion of uric acid in man and demonstrate increased urate excretion with increasing urine flow in normal and hyperuricemic subjects. When pyrazinamide was administered and the results analyzed, on the basis of the filtrationreabsorptionsecretion hypothesis, increased urate excretion appeared to result from enhanced tubular secretion of urate. Since activation of a secretory transport system for urate by water ingestion is improbable, these findings provide evidence for modification of the currently accepted threecomponent hypothesis for renal handling of uric acid, and are consistent with the existence of a distal reabsorptive site for urate in man. Studies were carried out in a format adapted from that described by Steele and Rieselbach (6). Standard clearance technics were employed. The initial phase of each study involved two or three clearance periods of 10 to 50minute duration. Duration was varied to assure adequate urine volumes for accurate collection without catheterization. At the end of the final clearance period, each subject took 3 g of pyrazinamide orally. One hour later, the first of at least three additional clearance periods of similar duration to the initial periods was begun. Collections were continued for at least 1 additional hour. Maximum suppression of uric acid excretion after pyrazinamide was usually achieved in the second or third clearance period. Hernatocrits and weights were obtained hourly on each subject during each study. Two or more studies were carried out on each subject. In one study, water was administered in order to result in a low urine flow rate. A second study involved a water intake twice as great as that used in the first study. In 5 subjects, a third study was performed involving a still higher water intake or rapid saline infusion intended to produce expansion of extracellular fluid volume. Laboratory determinations were carried out in a Clinical Research Center laboratory. Uric acid determinations were performed by an automated enzymatic (uricase) spectrophotometric method (13). Glomerular filtration rate (GFR) was determined by either inulin (14 studies in 5 subjects) or creatinine clearance (15 studies in 7 subjects). lnulin was determined by a resorcinol method (14). Creatinine determinations were carried out using a standard automated technic (I 5). Sndium was measured by the automated technic described by Mabry el al (I 6). MATERIALS AND METHODS Twentynine renal clearance studies were performed on 12 subjects who ranged in age from 21 to 63 years. No subjert had blood urea nitrogen greater than 20 mg% or evidenke of renal disease by history or physical examination, although 2 subjects had diminished creatinine or inulin clearances (Table 1). Nine subjects were hyperuricemic; 8 had clinical gout. Three subjects were healthy adult males. All subjects were in good nutritional state and ambulatory at the time the tests were conducted. None were acutely ill. All medications affecting serum uric acid levels were withdrawn at least 4 days prior to studies. All patients were studied after at least 3 days on a lowpurine, lowprotein, isocaloric diet. Studies were carried out in the morning after a 12hour fast. Sufficient fluid was administered to establish the desired steady state of urine flow, and flow rate was then maintained by constant oral intake or intravenous fluid administration using a constant flow infusion pump. With the exception of three saline infusion studies, oral fluid was given as water and intravenous fluid as 5% glucose in water. Calculations The use of pyrazinamide to study renal handling of uric acid in man has been previously described (6, 17). Urate excretion was determined during the clearance periods before administration of pyrazinamide. The fraction of control urate excretion contributed by tubular secretion was calculated by subtracting the mean urate exrretion during the clearance period showing maximum suppression of urate secretion after pyrazinamide from the mean urate excretion before pyrazinamide. Urate excretion at the time of maximal pyrazinamide induced suppression was used as a maximal estimate of the component of urate excretion provided by urate filtered and not reabsorbed. This value was subtracted from the filtered urate (filtered urate = GFK multiplied by serum urate concentration) to determine the rate of urate reabsorption. The percent of filtered urate reabsorbed was calculated by dividing reabsorbed urate by filtered urate. These calculations are based on the assumption that pyrazinamide produces essentially complete suppression of tubular secretion of urate with little or no effect on urate filtration or reabsorption. The data supporting this assumption have been summarized previously (17). Arthritis and Rheumatism, Vol. 15, No. 4 (JulyAugust 1972) 339

3 Table 1. Results of 29 Clearance Studies in 12 Subjects CUJ Post PZA V GFR Fur UUJ Cur Sur Uurv U u rv/ Sur/ Surl Patient (ml/min) (ml/min) (mg/min) (rg/min) (ml/min) (pg/min) (ag/min) %R GFR GFR U,rV GFR WL AR JR SL DR LW SM RG HD JP TC E D 5.30 = B V = urine flow rate: GFR = glomerular filtration rate: Fur = filtered urate: UurV = Urinary uric acid excretion; Cur = urate clearance; Sur = secreted urate; Post PZA Uu,V = urinary uric acid excretion after pyrazinamide administration; % R = urate reabsorption 0 7? ~

4 URINE ACID EXCRETION Statistical Analysis Results in the text are expressed as mean and standard error of the mean (SEM). Differences between values obtained in the same subject studied at increased and decreased urine flow rates were compared using a 1 test for paired variables. A difference was considered significant if thepvalue was c.05. RESULTS The results of 29 clearance studies performed on 12 subjects are summarized in Tables 1 and 2. In the study at the lowest rate of urine flow for each subject, mean urate excretion for 12 subjects was 290 f 43 pg/min at a mean rate of urine flow of 2.7 * 0.6 ml/min. Urate excretion increased to 410 * 52 pg/min when urine flow was 6.4 f 0.9 ml/min (P <.01). In the 5 subjects who had a third study performed at a still greater urine flow (12.1 ml/min), urate excretion increased again to 692 pg/min. There was no significant change in plasma urate levels. Changes in urate clearance (Cur) were thus proportionate to the increment in urate excretion. There was no significant change in GFR at the lower and higher flow rate, although GFR increased slightly at the higher flow rate (Table 2). The increment in urate excretion was not accounted for by the observed increase in GFR, since urate excretion/gfr increased from 2.93 f 0.35% to 3.79 f 0.40% (P <.005) (mean of first and second studies), and mean Cur/GFR x 100 increased from 4.09 f 0.56% to 5.89 f in the same studies (P <.01). In the 5 subjects studied a third time, the results were similar, mean urate excretion/gfr increasing from 3.95 to 5.12 pg/ml and Cur/GFR x 100 increasing from 4.92 to 6.79%. Changes in filtered urate load paralleled GFR (7.66 f 1.07 mg/min in the initial study and mg/min in the second study) and were not significantly different (P >.lo). The changes were larger in the 5 subjects studied a third time, reflecting the larger increment in GFR. Pyrazinamide was administered at least twice to 11 of the 12 subjects, and a third time to 4 subjects. In these subjects, it was possible to analyze the relative contributions of reabsorption and secretion to the observed changes in urate clearance. Mean postpyrazinamide urate excretion increased, but not significantly (P >.05), rising from 36 f 4 pg/min at the lower flow rate study to 57 f 13 pg/min at a higher flow rate, accounting for only 18% of the observed increase in urate excretion. Nor was there a significant change (P >.05) in the percent of the filtered urate load reabsorbed, as urate reabsorption closely paralleled filtration (percent reabsorption % in the lower flow rate study and % in the higher flow rate study). Thus, the ma.jor portion of the increment in urate excretion was not accounted for by changes in urate filtration or reabsorption and is attributed to increased urate secretion. In the 11 pairs of studies, mean urate secretion increased from pg/min in the initial study to 339 f 47 pg/min at the greater urine flow (P <.Ol), accounting for 80% of the increase in urate excretion. In the 4 subjects who underwent a third clearance study using pyrazinamide, urate secretion increased again, going from a mean of 352 pg/min at a urine flow of 5.3 ml/min to 455 pg/min when urine flow was 8.8 ml/min, and accounted for 65% of the observed change in urate excretion. Postpyrazinamide mate excretion in the same studies increased from 43 to 98 pglmin, and percent reabsorption decreased from to 99.08%. Thus, failure of reabsorption appeared to account for a larger fraction of the increment in urate excretion in these studies. The increment in urate secretion was not accounted for by an increase in GFR since urate secretion/gfr increased significantly from 2.50 f 0.37 pg/ml to pg/ml (P <.01). Changes in extracellular fluid volume were followed by measuring hematocrit and body weight hourly during each clearance study. Arthritis and Rheumatism, Vol. 15, No. 4 (JulyAugust 1972) 341

5 DIAMOND ET AL Table 2. Comparison of Results of Decreased Urine Flow (Study 1) and Increased Urine Flow (Study 2) in 12 Subjects* Study 1 Study 2 Mean SEM Mean SEM Jt V (ml/rnin) GFR (ml/min) NS F, (mglrnin) NS Uurv (rdmin) C,,(rnl/m i n) S, (dmin) Post PZA U,V (pglrnin) NS 9'0 R NS U,V/G FR S,,/GFR SudUurV NS C,,/G FR *See footnote to Table 1 for abbreviations. t 1 test of paired variables NS (Not significant) means P >.05 There was no significant change in hematocrit during any of the studies. There was no consistent trend in body weight during either the 12 studies at the lowest flow rate or the 12 studies at the next greater flow rate. Mean weight gain during the clearance study was kg in the initial study and kgduring the second study. There was no significant weight gain in either set of studies. Steele has observed a significant increase in postpyrazinamide urate excretion following expansion of extracellular fluid volume (18), indicating decreased urate reabsorption under these conditions. Only 2 subjects (SM and HD) gained more than 1 kg of weight during the second study. Neither subject had shown weight gain in their initial study. These 2 subjects had the lowest values for percent reabsorption (99.00 and 97.08%) of the 11 subjects studied. SL gained more than 1 kg during the third study. Again, percent reabsorption decreased from to , and postpyrazinamide urate excretion rose from 44 to 133 rg/min. Because these findings suggested that significant expansion of extracellular fluid volume might result in a decreased rate of urate reabsorption (as reported by Steele), in 3 subjects, a third clearance study was performed using saline infusion to produce expansion of the extracellular fluid volume. In 2 subjects (LW and SM), extracellular fluid volume expansion was produced in Study 3 by intravenous infusion of isotonic saline at a rate of 15 ml/min. In LW, urine flow increased from 6.4 (Study 2) to 12.0 rnl/min, and urate excretion increased from 446 to 604 rg/min. Postpyrazinamide urate excretion nearly tripled from 34 to 101 pg/min, and percent reabsorption decreased from to 99.23%. Urate secretion/urate excretion x 100 decreased from 92.4 to , although urate secretion also increased from 412 to 503 rg/ min. In SM, where volume expansion was accompanied by only a minimal change in urine flow from 4.8 to 5.1 ml/min and a weight gain of 1.6 kg, urate secretion changed only slightly, increasing from 245 to 288 pg/min. An increase in postpyrazinamide urate excretion from 37 to 82 gg/min accounted for more than 342 Arthritis and Rheumatism, Vol. 15, No. 4 (JulyAugust 1972)

6 URINE ACID EXCRETION 50% of the increment in urate excretion (from 282 to 370 ccg/min). Percent reabsorption decreased from to 98.42%, and urate secretion/urate excretion x 100 decreased from 86.9 to 77.8%. This is consistent with Steele s observation that urate excretion and secretion do not change significantly during volume expansion under conditions in which urine flow is constant (19). In subject TC, 2.5% saline was infused at a rate of 15 ml/min in Study 3. This subject had the largest weight gain recorded (3.6 kg). Urine flow rate rose to 25 ml/min, and Cur increased from 6.2 to 20.3 ml/min. Pyrazinamide was not administered, so the relative contribution of secretion and reabsorption to this change could not be calculated. DISCUSSION The present study demonstrates a direct relationship between urine flow rate and urate excretion; urate excretion increased in direct proportion to increased water excretion produced by oral or intravenous hydration with electroytefree solutions. The increased urate excretion was largely due to a proportionate increase in apparent secretion of urate by the renal tubule. This increase was observed in the absence of significant change in extracellular fluid volume as measured by body weight and hematocrit. Although urate reabsorption decreased slightly in the same studies, this did not account for the major portion of the increment in urate excretion. Changes in GFR did not account for the observed increment in urate excretion since Cur/GFR, urate excretion/gfr and urate secretion/gfr all increased as urine flow rate increased. The possibility that the observed differences in urate excretion were due to factors other than differences in urine flow rate should be considered. Since tubular secretion of urate varies directly with plasma urate concentration, an increase in plasma urate concentration could result in increased urate excretion. However, plasma urate levels were not significantly different for the group as a whole during Study 1, as compared to Study 2. In fact, in 3 subjects, (WL, DR and HD) urate excretion increased at higher flow rate, although plasma urate levels fell. Subjects in this study were not catheterized. If bladder emptying were incomplete, this could introduce an error in the calculated urate excretion and clearance, particularly in studies conducted at the lowest urine flow rate. The glomerular filtration rate was measured for each clearance period used in these calculations. Thus, calculations of urate excretion/ GFR, urate clearance/gfr and urate secretion/gfr are based only on urine and plasma concentrations and would not be affected by small errors in urine collection. As already noted, all three measures increased significantly (Table 2) as urine flow rate increased. Urate clearance/gfr in the initial studies reported here was 4.170, as compared to the finding by Steele and Rieselbach (6) of a urate clearance/gfr of 9.8% in a series of normal subjects studied by the same technic. This suggests that the subjects studied here were hyposecretors of urate and their response to flow rate changes might be atypical. However, urate clearance/gfk in this study was determined at a mean urine flow rate of 2.7 ml/min and was flow rate dependent, increasing to 5.9% when flow rate was 6.7 ml/min. The normal subjects, reported as having urate clearance/gfr of 9.870, were studied at still higher flow rates of 7 to 15 ml/min (6). Thus, the apparent low values for urate clearance and urate clearance/ GFR in the present study are more likely a reflection of the increase in urate clearance with increasing urine flow rate rather than an indication of marked hyposecretion. Expansion of extracellular fluid volume results in increased excretion of uric acid, most electrolytes and some small molecules (19). Extracellular fluid volume expansion has been shown by Steele to result in a decrease in tubular reabsorption of filtered urate (18). When urine flow rate was held constant, total urate Arthritis and Rheumatism, Vol. 15, No. 4 (JulyAugust 1972) 343

7 DIAMOND ET AL excretion showed little change. The observations reported here differ from those of Steele in that increased urate excretion was observed in the absence of significant extracellular fluid volume expansion when flow rate was allowed to increase. Since the major mechanism for increased urate excretion was enhanced tubular secretion rather than decreased reabsorption, it is unlikely that unmeasured small increases in extracellular fluid volume could account for the increase in urate excretion observed in the present studies. In those studies in which considerable volume expansion was induced, decreased urate reabsorption was observed, confirming the observations reported by Steele. Osmotic diuresis produced by administration of mannitol (10) or glucose (10, 12) produced increased excretion of uric acid. Three subjects in the present study (LW, SM and TC) received intravenous 5% glucose infusion to induce a water diuresis. It is unlikely that the increased urate excretion observed was due to a uricosuric effect of glucose since these subjects received glucose infusions in both studies; the additional glucose infused in the high flow rate study was only 25 g and no subject developed glycosuria. Urate diuresis due to glucose infusion cannot explain the overall results of this study, since urate excretion increased significantly (P <.01) at higher flow rate in the 9 subjects in whom water diuresis was induced by increased oral intake of water. The increased uric acid excretion produced by glucose infusion is not completely explained by osmotic load since glucose infusion produced a greater increase in uric acid excretion for an equivalent osmolar load than does mannitol (10). Since, in the studies cited, at equivalent osmolar loads, glucose infusions resulted in a higher urine flow than mannitol infusion, this difference may have been related to flow rate. Several other studies are consistent with a relationship between distal tubular flow and uric acid excretion. For example, infusion of angiotensin sufficient to raise diastolic pressure 20 mm Hg results in decreased urine flow and a proportionate decrease in urate excretion (11). Changes in renal plasma flow have been suggested as a mechanism for proportionate alteration in urate excretion (11). Although renal plasma flow was not measured in the studies reported here, water loading is unlikely to have produced increased renal plasma flow sufficient to account for the results. Steele found only small, inconsistent changes in paraaminohippuric acid (PAH) clearance when saline was infused to expand extracellular fluid volume (18). Changes in PAH clearance tended to be proportionate to changes in GFR and, thus, did not account for Steele s findings. Paraaminohippuric acid clearance may not be a suitable measure of renal blood flow in urate clearance experiments, since, at least in the cebus monkey, PAH is a competitive inhibitor of urate secretion (19). The evidence for alteration of urate secretion by urine flow rate is based on the assumption that pyrazinamide administration results in selective inhibition of tubular secretion of uric acid without altering urate reabsorption. Recent experiments in the cebus monkey have been interpreted as suggesting that pyrazinamide may increase urate reabsorption (20). If this interpretation is proven correct, the analysis of the results of this study and other studies employing the pyrazinamide technic will require revision. It is difficult to explain the present results on the basis of the threecomponent (filtrationsecretionreabsorption) hypothesis for renal handling of uric acid, since this mechanism requires accepting the concept that water ingestion or increased water clearance results in activation of the tubular transport system for uric acid. Although this is theoretically possible, it seems unlikely. Osmotic diuretics, such as mannitol and glucose, increase renal cortical blood flow, as well as urine flow rate, and are known to be uricosuric (10). Infusion of epinephrine and angiotensin, which are known to result in de 344 Arthritis and Rheumatism, Vol. 15, No. 4 (JulyAugust 1972)

8 URINE ACID EXCRETION creased perfusion of cortical nephrons and decreased urine flow, produce renal retention of uric acid (11). Similarly, intravenous ethacrynic acid acutely results in increased cortical blood flow (21) and simultaneous increase in urate excretion (22). Although these results are consistent with the hypothesis that cortical nephrons have an increased secretory capacity for urate, there is no direct evidence for this suggestion. Moreover, there is no evidence that cortical blood flow increases during water diuresis. An increased rate of urine flow induced by oral water ingestion in the absence of volume expansion should produce no change in proximal tubular flow as long as glomerular filtration rate is constant. The increased flow produced under these conditions results from dilution occurring in the distal tubule and collecting duct. It is therefore not surprising to find no change in urate reabsorptiona proximal tubular function, under these circumstances. If there be a second, distal tubular reabsorptive site for urate, this site might be affected by dilution; the increased urine flow might result in decreased time for reabsorption of urate and, thus, increased urate excretion. Since this site is distal to the secretory site blocked by pyrazinamide, administration of this drug would not distinguish between increased tubular secretion and decreased reabsorption at a hypothetical postsecretory reabsorptive site. Thus, the results of this study are consistent with the existence of a distal, postsecretory reabsorptive site for urate in man. REFERENCES 1. Gutman AB, Yu TF: A threecomponent system for regulation of renal excretion of urate in man. Trans Assoc Am Physicians 74:353365, Yu TF, Gutman AB: Ultrafiltrability of plasma urate in man. Proc Soc Exp Biol Med 84:21 24, Berliner RW, Hilton JG, Yu TF, et al: The renal mechanism for urate excretion in man..j Clin Invest 29:396401, Yu TF, Berger L, Stone DJ, et al: Effect of pyrazinamide and pyrazinoic acid on urate clearance and other discrete renal functions. Proc SOC Exp Biol Med 96:264267, Gutman AB, Yu TF, Berger L: Tubular secretion of urate in man. *J Clin Invest 38: , Steele TH, Rieselbach RE: The renal mechanism for urate homeostasis in normal man. Am J Med , Yu TF, Berger L, Gutman AB: Suppression of tubular secretion of urate by pyrazinamide in the dog. Proc SOC Exp Biol Med 107:905908, Gregor R, Lang F, Deetjen P: Handling of uric acid by the rat kidney. I. Microanalysis of uric acid in proximal tubular fluid. Pfluegers Arch 324:279287, BrochnerMortenson K: Uric acid in blood and urine. Acta Med Scand (Suppl) 84: 1269, Skeith MD, Healy LA, Cutler RE: Urate excretion during mannitol and glucose diuresis. J Lab Clin Med70:213220, Ferris TF, Gordon P: Effect of angiotensin and norepinephrin upon urate clearance in man. Am J Med 44:359365, Bonsnes RW, Dana ES: On the increased uric acid clearance following the intravenous infusion of hypertonic glucose solution. J Clin Invest , Crowley LV, Alton FT: Automated analysis of uric acid. Am J Clin Pathol49:285288, Roc JF, Epstein JH, Goldstein NP: A photoelectric method for the determination of inulin in plasma and urine. J Biol Chem 178: , Technicon Autoanalyzer Methodology. Method File No. 11 b 16. Mabry CC, Geveden RE, Tochel IF, et al: Submicro automation of a central clinical chemistry laboratory. Automation in Analytical Chemistry. Vol. 1. Technicon Symposium, Medical Corp, 1967, p Gutman AB, Yu TF, Berger L: Kenal function in gout Estimation of tubular secretion and reabsorption of uric acid by use of pyrazinamide (pyrazinoic acid). Am J Med 47:575592, 1969 Arthritis and Rheumatism, Vol. 15, No. 4 (JulyAugust 1972) 345

9 DIAMOND ET AL 18. Steele TH: Evidence for altered renal urate Cebus monkey. Am J Physiol 218:627636, reabsorption during changes in volume of the 1970 extracellular fluid..j Lab 'Iin Med 74: , Cannon PJ, Svahn DS, DeMartini FE: The influence of hypertonic saline infusions upon the fractional reabsorotion of urate and other ions in normal and hypertensive man. Circulation 21, Birtch AG, Zakheim RM,.Jones LG, et al: Redistribution of renal blood flow produced by furosemide and ethacrynic acid. Circ Res 21:869878, Cannon PJ, Heinemann HO, Stason WB, et al: 41:97108,1970 Ethacrynic acid. EFfectiveness and mode of 20. Fanelli GM, Boh D, Stafford S: Functional diuretic action in man. Circulation 31 :518, characteristics of renal urate transport in the 1965 REVISED DEADLINE FOR ABSTRACTS The deadline for receipt of abstracts of papers to be presented at the Interim Scientific Meeting on December 8 and 9,1972, in Pittsburgh has been extended. Abstracts should be postmarked no later than midnight Friday, September 8, The original abstract deadline of August 25, 1972 was published in the MayJune issue of ARTHRITIS AND RHEUMATISM. 346 Arthritis and Rheumatism, Vol. 15, No. 4 (JulyAugust 1972)